In 1998, Andersen et al reported the discovery of the motuporamine family of compounds from the sea sponge Xestespongia exigua off the coast of Motupore Island in Papua New Guinea.36 These compounds were of particular interest as they each possessed a large macrocycle tethered to a norspermidine (3,3-triamine) message. This class of drug was structurally similar to anthryl-polyamines previously reported by Phanstiel et. al.9,36 Biologically, dihydromotuporamine C (44a) proved to be the most interesting as it was highly cytotoxic to the MDA-231 breast carcinoma cells and had good anti-invasive properties.36-37 Due to the motuporamine compounds exhibiting structural similarities to 5a (Ant33) and other analogues made previously in our lab9, it was thought that they may function in a similar manner to anthryl-polyamine conjugates. Structures of motuporamine natural products (41, 42, 43, 44a) and dihydromotuporamine C mimic (45) and Ant33 (5a) are as follows:

Note: the Ring size is noted by the number inside the macrocycle.
Recently, it has been shown that dihydromotuporamine C (44a) affects the sphingolipid biosynthetic pathway.38 Baetz et. al initially showed through a genome-wide haploinsufficiency screen in yeast that dihydromotuporamine C targets sphinoglipid metabolism.38a This was demonstrated via the recognized sensitivity of genes LCB1 and TSC10 to the addition of dihydromotuporamine C. Both are key genes involved in the biosynthesis of sphingosine, which is a sphingolipid precursor.38a This was the first molecular target described for 44a. The authors went on to demonstrate that dihydromotuporamine C at 60 μM was able to fully inhibit the growth of yeast cells.39 However, the addition of an intermediate of the sphingosine and ceramide pathway (dihydrosphingosine) to dihydromotuporamine C-treated yeast cells, was able to rescue this growth inhibition.39 While it was shown that dihydromotuporamine C directly lowers the levels of ceramide, the addition of exogenous ceramide was able to partially rescue yeast growth indicating that dihydromotuporamine directly targets sphingolipid biosynthesis.38 Despite this finding in yeast, it could not be demonstrated that exogenous ceramide could completely rescue the effects of dihydromotuporamine C.38a,b This observation could be explained by dihydromotuporamine C having multiple targets in human cells or that the rescue event was limited by the amount of ceramide that could be added as ceramide is known to have pro-apoptotic properties.38a,b The fact that the less toxic dihydrsphingosine could rescue these cells is consistent with the latter possibility.
Beyond sphingolipid metabolism, Rho GTPase was also identified as a target of dihydromotuporamine C (44a).38b An increase in Rho signaling has been associated with many types of cancer.40 This increase in Rho signaling has also seen to play a part in the anti-invasive action of dihydromotuporamine C.38b,41 This has been partly explained by a loss of cell polarity and an increase in adhesion strength caused by Rho activation.38b Another key player in the anti-migration ability of dihydromotuporamine C is the activation of integrin signaling, which in turn leads to the inhibition of tumor migration by activated Rho signaling.38b, 42 
A series of structure activity relationship studies has also helped determine which aspects of dihydromotuporamine C's (44a) structure provides its unique biological activity. The structure of the motuporamines can be broken into two main areas: the macrocyclic ring, and the norspermidine tail. It has been shown that the 15-membered macrocyclic ring is favored over other size rings as it demonstrated the highest levels of cytotoxicity and invasion inhibition in MDA-MB-231 cells.37a Williams et. al. also showed that the degrees of unsaturation in the ring also dramatically affected the biological activity of the series, where a saturated ring (completely void of unsaturation) proved to be most biologically interesting in terms of anti-migration properties.37a A carbazole ring substitute also showed promising anti-invasion properties, although it was not as potent as the parent, dihydromotuporamine C.37a 
The other key structural characteristic of the motuporamines is the norspermidine tail. It was demonstrated that acetylation of the terminal amino group had no effect on the biological activity of motuporamine C (43), however, acetylation of both amine groups saw a complete loss of activity.37b This finding points to the importance of the central secondary amine for these compounds to exhibit high biological activity.
Previous efforts by Phanstiel et. al. explored the conformational preferences of dihydromotuporamine C (44a) by computer modeling.43 These experiments demonstrated that the saturated ring system was conformationally mobile as expected. The orientation of the polyamine chain off the ring was shown to be critical and helped the authors design new motuporamine mimics These mimics were predicated upon anthryl-polyamines Specifically, AntNEt33 (45) had similar computed molecular conformation preferences to dihydromotuporamine C (44a) and was shown to mimic the cytotoxicity of dihydromotuporamine C in CHO and CHO-MG. See U.S. Pat. No. 7,728,041, the entirety of which is hereby incorporated by reference. Also ref: “Modeling the Preferred Shapes of Polyamine Transporter Ligands and Dihydromotuporamine-C Mimics: Shovel versus Hoe,” Breitbeil III, F. Kaur, N.; Delcros, J-G.; Martin, B.; Abboud, K. A.; Phanstiel, I V, O. J. Med. Chem. 2006, 49, 2407-2416. Although AntNEt33 (45) was a good mimic of dihydromotuporamine C in vitro, it failed to mimic the anti-metastatic properties of dihydromotuporamine C in vivo.